The goal of this research is to provide a better understanding of the pharmacological effects of antidepressant treatments, when administered over time, on central biogenic amine neuronal systems. This would be expected to lead to an improved understanding of the biology of affective illnesses and toward improved treatment of these illnesses. In particular, we intend to study whether chronic treatment of rats with a variety of established and newer antidepressant treatments causes the development of Beta-adrenerigc receptor subsensitivity. Beta-adrenergic receptors will be studied with the use of the radioactive Beta-adrenergic antagonist (-)3H-dihydroalprenolol (3H-DHA). We have found already that treatment of rats with a number of different antidepressant drugs lowers 3H-DHA binding to cerebral cortical homogenates, and that some other classes of psychoactive drugs do not have this effect. We intend to expand this line of investigation to determine whether the lowering of 3H-DHA binding can be used as a pre-clinical screen for antidepresssant activity. In addition, experiments are planned that should provide some information on the clinical relevance of the antidepressant drug-induced development of central Beta-adrenergic receptor subsensitivity. An expansion of this type of investigation will be our use of 3H-5hydroxytryptamine (serotonin) to label central serotonergic receptors so as to investigate the effects of repeated treatment of rats with different types of psychotropic drugs on these receptors. The pineal gland will be used to measure the effect of antidepressant treatments on adrenergic responsiveness both in vivo and in vitro. Catecholamines will be administered exogenously to rats treated either acutely or chronically with antidepressant drugs and the concentration of adenosine 3', 5' monophosphate (cyclic AMP) in the pineal gland measured. In addition, the abiliy of acute and chronic treatment of rats with desmethyl-imipramine to modify adrenergic responses in the pineal gland caused by norepinephrine released endogenously from the sympathetic nerve innervating the pineal gland will be studied.